Nanoparticles (NPs) have been widely pursued as a promising tool to increase the biodistribution of anti-cancer therapeutics in tumors, thereby reducing the general exposure to chemotherapy. It is generally acknowledged that defective vasculature and lymphatic systems surrounding tumors offer a selective opportunity for NPs to accumulate in tumors. However, the amount delivered to tumors this way is only a small fraction (~5%) of the total administered NPs. This challenge may be addressed by decorating the surface of NPs using a tumor-specific ligand, but the benefit is often limited due to the heterogeneity and genetic instability of tumors. Challenges in drug delivery using NPs are aggravated by the limited penetration of NPs into tumors, due to high tissue stiffness and interstitial fluid pressure. Substantive departure from the status quo NP-based drug delivery requires a new strategy to increase the amount of NPs delivered to and retained by tumors beyond the level currently possible based on passive delivery via the so-called enhanced permeability and retention (EPR) effect or other targeting strategies. Our long term goal is to develop a new drug delivery strategy that enhances delivery of nanomedicine into solid tumors to a greater extent than currently achieved. The objective of this application is to enhance the accumulation, retention, and penetration of anti-cancer drugs into solid tumors, via synergistic application of environmentally-adaptive NPs (ENPs) and image-guided radiation-induced permeability (IGRIP). Our central hypothesis is that NPs developing cationic surface or reduced size specifically in tumors will be better retained and/or penetrated in tumors than conventional non-adaptive NPs, and tumor accumulation of such NPs will be actively increased by targeted irradiation that results in local increase of microvascular permeability. The rationale for this project is that its successful completion will enable the delivery of a greater amount of anti- cancer therapeutics to solid tumors than currently achieved with existing technology, thereby enhancing the effectiveness of cancer therapy. We will achieve our objective by pursuing the following three specific aims, where we will optimize the synthesis of ENPs and encapsulation of a model anti-cancer drug, paclitaxel (PTX) (Aim 1) and validate the IGRIP effect in a mouse model of prostate cancer (Pica) and optimize the irradiation regimen for NP delivery (Aim 2). Based on the optimized ENPs and irradiation regimen, we will correlate the pharmacokinetics and biodistribution of PTX delivery and anti-tumor effects in mice with Pica, to test the effectiveness of ENPs in PTX delivery to tumors as compared to Abraxane and the IGRIP enhancement of ENP delivery (Aim 3). By the completion of this study, we expect to have confirmed our approach as a valid methodology to increase biodistribution of nanomedicine into solid tumors and enhance therapeutic potential.